Project Summary Type 2 diabetes (T2D) afflicts 9% of the global population and is projected to affect 30% by 2050 if current trends continue. Recent reviews by the National Toxicology Program and World Health Organization indicate that this rise in T2D cannot be attributed solely to the increasing rate of obesity. Exposure to obesogenic and/or diabetogenic chemicals, alone or in conjunction with other environmental and lifestyle factors, may play a contributing role. Numerous population studies have found an association between exposure to inorganic arsenic (iAs) in drinking water and an increased incidence or prevalence of diabetes. These studies also indicate that metabolism of iAs (i.e. that facilitates clearance of iAs from the body) influences individual susceptibility to adverse effects of iAs exposure. Metabolism of iAs in humans occurs through enzymatic methylation, catalyzed by arsenic methyltransferase (AS3MT). Polymorphisms in AS3MT are associated with differences in iAs metabolism and with indicators of T2D. Methylation of iAs utilizes S-adenosylmethionine for methyl groups and folate is a dietary micronutrient that is required for SAM synthesis. Population studies find that high folate intake is associated with a more efficient iAs metabolism and decreased iAs toxicity. Thus, the efficiency of iAs metabolism, modifiable by polymorphisms in AS3MT or folate intake, may play an important role in the diabetogenic effects of iAs exposure. The proposed research will examine the role of iAs metabolism in the diabetogenic effects of iAs exposure, by studying As3mt-KO mice that cannot methylate iAs and restricting folate intake to decreased efficiency of iAs metabolism in wild-type mice. Additionally, this project will probe underlying mechanisms of iAs-associated diabetes, investigating effects on insulin secretion, insulin resistance, and promoter methylation of diabetes- associated genes. Preliminary studies found that As3mt-knockout mice, that do not methylate iAs, developed insulin resistance and obesity after exposure to moderate levels of iAs (~80-139 ppb) through laboratory diet. These data suggest that impaired iAs metabolism results in a diabetogenic phenotype. Thus, the specific aims of this project are to: 1. Compare the diabetogenic effects of low (~10 ppb) and moderate (~80-139 ppb) iAs exposures in As3mt- knockout mice. 2. Characterize iAs metabolism and the diabetogenic effects of iAs exposure in wild-type mice with restricted folate intake. Data on the role of iAs metabolism in the diabetogenic effects of iAs exposure and underlying mechanisms will facilitate risk assessment of iAs-associated diabetes and will inform strategies for prevention or treatment (such as dietary supplementation) of this disease in susceptible populations.